scholarly journals Accumulation of Plasmodium berghei-Infected Red Blood Cells in the Brain Is Crucial for the Development of Cerebral Malaria in Mice

2010 ◽  
Vol 78 (9) ◽  
pp. 4033-4039 ◽  
Author(s):  
Fernanda G. Baptista ◽  
Ana Pamplona ◽  
Ana C. Pena ◽  
Maria M. Mota ◽  
Sylviane Pied ◽  
...  
Keyword(s):  
T Cells ◽  
Red Blood Cells ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Blood Cells ◽  
Human Infection ◽  
Experimental Cerebral Malaria ◽  
Human Pathology ◽  
The Brain ◽  
Malaria Model

ABSTRACT Cerebral malaria is the most severe complication of human infection with Plasmodium falciparum. It was shown that Plasmodium berghei ANKA-induced cerebral malaria was prevented in 100% of mice depleted of CD8+ T cells 1 day prior to the development of neurological signs. However, the importance of parasites in the brains of these mice was never clearly investigated. Moreover, the relevance of this model to human cerebral malaria has been questioned many times, especially concerning the relative importance of leukocytes versus parasitized erythrocytes sequestered in the brain. Here, we show that mice protected from cerebral malaria by CD8+ T-cell depletion have significantly fewer parasites in the brain. Treatment of infected mice with an antimalarial drug 15 to 20 h prior to the estimated time of death also protected mice from cerebral malaria without altering the number of CD8+ T cells in the brain. These mice subsequently developed cerebral malaria with parasitized red blood cells in the brain. Our results clearly demonstrated that sequestration of CD8+ T cells in the brain is not sufficient for the development of cerebral malaria in C57BL/6 mice but that the concomitant presence of parasitized red blood cells is crucial for the onset of pathology. Importantly, these results also demonstrated that the experimental cerebral malaria model shares many features with human pathology and might be a relevant model to study its pathogenesis.

Establishment of a murine model of cerebral malaria in KunMing mice infected with Plasmodium berghei ANKA

Parasitology ◽  
2016 ◽  
Vol 143 (12) ◽  
pp. 1672-1680 ◽  
Author(s):  
YAN DING ◽  
WENYUE XU ◽  
TAOLI ZHOU ◽  
TAIPING LIU ◽  
HONG ZHENG ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
Clinical Signs ◽  
Necrosis Factor Alpha ◽  
Experimental Cerebral Malaria ◽  
Km Mice

SUMMARYMalaria remains one of the most devastating diseases. Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection resulting in high mortality and morbidity worldwide. Analysis of precise mechanisms of CM in humans is difficult for ethical reasons and animal models of CM have been employed to study malaria pathogenesis. Here, we describe a new experimental cerebral malaria (ECM) model with Plasmodium berghei ANKA infection in KunMing (KM) mice. KM mice developed ECM after blood-stage or sporozoites infection, and the development of ECM in KM mice has a dose-dependent relationship with sporozoites inoculums. Histopathological findings revealed important features associated with ECM, including accumulation of mononuclear cells and red blood cells in brain microvascular, and brain parenchymal haemorrhages. Blood–brain barrier (BBB) examination showed that BBB disruption was present in infected KM mice when displaying clinical signs of CM. In vivo bioluminescent imaging experiment indicated that parasitized red blood cells accumulated in most vital organs including heart, lung, spleen, kidney, liver and brain. The levels of inflammatory cytokines interferon-gamma, tumour necrosis factor-alpha, interleukin (IL)-17, IL-12, IL-6 and IL-10 were all remarkably increased in KM mice infected with P. berghei ANKA. This study indicates that P. berghei ANKA infection in KM mice can be used as ECM model to extend further research on genetic, pharmacological and vaccine studies of CM.

scholarly journals Eosinophils Suppress the Migration of T Cells Into the Brain of Plasmodium berghei-Infected Ifnar1-/- Mice and Protect Them From Experimental Cerebral Malaria

2021 ◽  
Vol 12 ◽  
Author(s):  
Johanna F. Scheunemann ◽  
Julia J. Reichwald ◽  
Patricia Jebett Korir ◽  
Janina M. Kuehlwein ◽  
Lea-Marie Jenster ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Type I ◽  
Experimental Cerebral Malaria ◽  
Cell Responses ◽  
The Brain

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1-/- mice and wild type mice suffering from ECM. Importantly, CD8+ T cells were increased in the spleens of ECM-protected Ifnar1-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+ T cell infiltration into the brain and increased ECM induction in PbAAma1OVA-infected Ifnar1-/- mice. However, eosinophil-depletion did not reduce the CD8+ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+ T cell migration and proliferation during PbAAma1OVA-infection in Ifnar1-/- mice and thereby are contributing to the protection from ECM.

scholarly journals CD8+ T Cells and IFN-γ Mediate the Time-Dependent Accumulation of Infected Red Blood Cells in Deep Organs during Experimental Cerebral Malaria

PLoS ONE ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. e18720 ◽  
Author(s):  
Carla Claser ◽  
Benoît Malleret ◽  
Sin Yee Gun ◽  
Alicia Yoke Wei Wong ◽  
Zi Wei Chang ◽  
...  
Keyword(s):  
T Cells ◽  
Red Blood Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Blood Cells ◽  
Time Dependent ◽  
Experimental Cerebral Malaria ◽  
Ifn Γ

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals IFN-γ–Producing CD4+ T Cells Promote Experimental Cerebral Malaria by Modulating CD8+ T Cell Accumulation within the Brain

2012 ◽  
Vol 189 (2) ◽  
pp. 968-979 ◽  
Author(s):  
Ana Villegas-Mendez ◽  
Rachel Greig ◽  
Tovah N. Shaw ◽  
J. Brian de Souza ◽  
Emily Gwyer Findlay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cerebral Malaria ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Experimental Cerebral Malaria ◽  
Cell Accumulation ◽  
Ifn Γ ◽  
The Brain

scholarly journals High Parasite Burdens Cause Liver Damage in Mice following Plasmodium berghei ANKA Infection Independently of CD8+T Cell-Mediated Immune Pathology

2011 ◽  
Vol 79 (5) ◽  
pp. 1882-1888 ◽  
Author(s):  
Ashraful Haque ◽  
Shannon E. Best ◽  
Fiona H. Amante ◽  
Anne Ammerdorffer ◽  
Fabian de Labastida ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Damage ◽  
Plasmodium Berghei ◽  
Clinical Symptoms ◽  
Neurological Symptoms ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Immune Pathology ◽  
The Brain

ABSTRACTInfection of C57BL/6 mice withPlasmodium bergheiANKA induces a fatal neurological disease commonly referred to as experimental cerebral malaria. The onset of neurological symptoms and mortality depend on pathogenic CD8+T cells and elevated parasite burdens in the brain. Here we provide clear evidence of liver damage in this model, which precedes and is independent of the onset of neurological symptoms. Large numbers of parasite-specific CD8+T cells accumulated in the liver followingP. bergheiANKA infection. However, systemic depletion of these cells at various times during infection, while preventing neurological symptoms, failed to protect against liver damage or ameliorate it once established. In contrast, rapid, drug-mediated removal of parasites prevented hepatic injury if administered early and quickly resolved liver damage if administered after the onset of clinical symptoms. These data indicate that CD8+T cell-mediated immune pathology occurs in the brain but not the liver, while parasite-dependent pathology occurs in both organs duringP. bergheiANKA infection. Therefore, we show thatP. bergheiANKA infection of C57BL/6 mice is a multiorgan disease driven by the accumulation of parasites, which is also characterized by organ-specific CD8+T cell-mediated pathology.

scholarly journals Mycobacterium tuberculosis Coinfection Has No Impact on Plasmodium berghei ANKA-Induced Experimental Cerebral Malaria in C57BL/6 Mice

2015 ◽  
Vol 84 (2) ◽  
pp. 502-510 ◽  
Author(s):  
Jannike Blank ◽  
Jochen Behrends ◽  
Thomas Jacobs ◽  
Bianca E. Schneider
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Parasite Clearance ◽  
Human Infection ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Cell Responses ◽  
The Tropics

Cerebral malaria (CM) is the most severe complication of human infection withPlasmodium falciparum. The mechanisms predisposing to CM are still not fully understood. Proinflammatory immune responses are required for the control of blood-stage malaria infection but are also implicated in the pathogenesis of CM. A fine balance between pro- and anti-inflammatory immune responses is required for parasite clearance without the induction of host pathology. The most accepted experimental model to study human CM isPlasmodium bergheiANKA (PbANKA) infection in C57BL/6 mice that leads to the development of a complex neurological syndrome which shares many characteristics with the human disease. We applied this model to study the outcome ofPbANKA infection in mice previously infected withMycobacterium tuberculosis, the causative agent of tuberculosis. Tuberculosis is coendemic with malaria in large regions in the tropics, and mycobacteria have been reported to confer some degree of unspecific protection against rodentPlasmodiumparasites in experimental coinfection models. We found that concomitantM. tuberculosisinfection did not change the clinical course ofPbANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. The immunological environments in spleen and brain did not differ between singly infected and coinfected animals; instead, the overall cytokine and T cell responses in coinfected mice were comparable to those in animals solely infected withPbANKA. Our data suggest thatM. tuberculosiscoinfection is not able to change the outcome ofPbANKA-induced disease, most likely because the inflammatory response induced by the parasite rapidly dominates in mice previously infected withM. tuberculosis.

scholarly journals Assessing Vascular Permeability during Experimental Cerebral Malaria by a Radiolabeled Monoclonal Antibody Technique

2001 ◽  
Vol 69 (5) ◽  
pp. 3460-3465 ◽  
Author(s):  
Henri C. van der Heyde ◽  
Philippe Bauer ◽  
Guang Sun ◽  
Wun-Ling Chang ◽  
Lijia Yin ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cerebral Malaria ◽  
Vascular Permeability ◽  
Plasmodium Berghei ◽  
Blue Dye ◽  
Vascular Endothelial ◽  
Antibody Technique ◽  
Experimental Cerebral Malaria ◽  
Endothelial Integrity ◽  
The Brain

ABSTRACT Vascular endothelial integrity, assessed by Evans blue dye extrusion and radiolabeled monoclonal antibody leakage, was markedly compromised in the brain, lung, kidney, and heart duringPlasmodium berghei infection, a well-recognized model for human cerebral malaria. The results for vascular permeability from both methods were significantly (P < 0.001) related.

scholarly journals Protein Kinase C θ Deficiency Increases Resistance of C57BL/6J Mice to Plasmodium berghei Infection-Induced Cerebral Malaria

2010 ◽  
Vol 78 (10) ◽  
pp. 4195-4205 ◽  
Author(s):  
Ariel Ohayon ◽  
Jacob Golenser ◽  
Rosa Sinay ◽  
Ami Tamir ◽  
Amnon Altman ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
Immune Responses ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Neurological Symptoms ◽  
Experimental Cerebral Malaria ◽  
Kinase C

ABSTRACT Protein kinase C θ (PKCθ) functions as a core component of the immunological synapse and serves as a key protein in the integrated T-cell antigen receptor (TCR)/CD28-induced signaling cascade leading to T-cell activation. However, the involvement of PKCθ in host-mediated immune responses to pathogens has not been thoroughly investigated. We tested the consequences of PKCθ ablation on the host response to infection by Plasmodium berghei ANKA (PbA). We found that both PKCθ+/+ and PKCθ−/− C57BL/6J mice are susceptible to infection with PbA. However, despite a similar parasite burden, PKCθ+/+ mice had an earlier onset of neurological signs, characteristics of experimental cerebral malaria (ECM), resulting in an earlier death. These mice suffered from an early and pronounced splenomegaly with a concomitant increase in the total number of CD4+ splenic T cells. In contrast, a large proportion of PbA-infected PKCθ−/− mice overcame the acute phase characterized by neurological symptoms and survived longer than PKCθ+/+ mice. The partial resistance of PKCθ−/− mice to ECM was associated with an impaired production of Th1-type cytokines, including gamma interferon and tumor necrosis factor alpha/lymphotoxin-α, which are known to exacerbate symptoms leading to ECM. In addition, PbA infection-induced LFA-1 expression in CD8+ T cells was suppressed in PKCθ-deficient T cells, suggesting a diminished ability to adhere to endothelial cells and sequester in brain microvasculature, which may explain the decrease in neurological symptoms. These data implicate PKCθ in CD4+ Th1+ and CD8+ T-cell-mediated immune responses during PbA infection that contribute to the development of ECM.

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